Epidemiology sheds new light on risk factors for ASD

Research using identical and fraternal twins is typically used to identify genetic influences on the development of ASD. This year, researchers studied a large group of twins and examined the concordance of different types of symptoms (1). Using this approach, the researchers found that the concordance of severe autism between identical twins and fraternal twins was about the same, indicating a strong environmental component to ASD severity. But what are those environmental factors? Epidemiological studies are providing clues.

At this year’s IMFAR, new data was presented that focused on studying groups of people and their exposures to a number of environmental factors. Each used different designs with their own unique advantages. For example, at UC Davis, the CHARGE study (www.beincharge.ucdavis.edu) examined the risk of developing autism following exposure to a number of factors that were identified through self report or medical records. Those that showed an association were antidepressant SSRI use (2) and metabolic disorders including hypertension and diabetes (3). On the other hand, a previously identified factor, maternal infection, was not associated (4). Why not? The researchers suggested that fever, not infection per se, may be a factor. Using self-report and medical records obtained prior to study entry may not accurately capture all relevant information, and an infection or fever may be missed in some reports. However, other types of information, such as method of birth, is easier to gather accurately. An analysis revealed that non-emergency or elective c-section deliveries did not show a significant association with autism, addressing a concern that many public and community stakeholders have expressed (5).

As an alternative to retrospective reports, the Early Markers of Autism Study in California is obtaining samples of blood from pregnant women by obtaining extra blood taken during the alpha-fetal protein screen that is banked. Not all states bank these samples for research, so this is a unique resource. By examining the levels of mercury in blood taken during pregnancy together with newborn blood spots, the researchers can get a more comprehensive picture of the prenatal environment. They reported no difference in mercury levels compared to those of non-affected children during gestation, and also reported no difference in thyroid hormone levels (6,7). Examination of subgroups of autism with regression did not change the results. While these data are incredibly novel and valuable, these studies were not designed to capture information throughout the entire pregnancy nor capture factors after birth

Another way to study exposures during pregnancy is through birth certificate data. In some states, the birth certificate contains information such as the place of birth and the occupation of the mother and the father. Using this information, scientists found that occupational exposures in mothers to certain chemicals resulted in an increased risk of ASD in offspring (8).

While each approach brings unique strengths, all researchers agree that the most comprehensive way to capture all information accurately, is a prospective design. This means identifying children as soon as possible and following them from that point on to gather every piece of relevant information from medical reports to blood samples. Autism Speaks is proud to co-sponsor such a study: the Early Autism Risk Longitudinal Investigation (EARLI). This groundbreaking project will provide even more answers to what causes autism, and needs the help of the community to do so.

So how can researchers blend or expand their research if they are using only one type of design? Autism Speaks and the National Institutes for Environmental Health Sciences are sponsoring a network of projects called the Environmental Epidemiology of Autism Research Network (EEARN). The goal of this network is to improve communication among researchers in this field, identify opportunities for collaborative projects and improve research tools for both existing, and new projects. Over 20 studies from 8 countries are represented in the network. We will keep you updated on the activity of the network, and we hope you will keep checking in for updates.

At last weeks 2011 IMFAR autism conference in San Diego the California Autism Twin Study (CATS) group presented its second of two oral presentations on their twin study data to date.

This paper concluded that autism does not appear to be the tail end of a normal distribution of autistic-like traits in the general population, a model promoted by genetic determinists such as John Constantino and Fred Volkmar but is instead a discrete clinical entity.

They also found that severity of autism is not heritable and that severity is likely to be the consequence of shared environmental factors.

I have discussed this with Sir Michael Rutter and we are in broad agreement with with respect to the three major twin studies, the CATS study, the IAN twin study have all replicated the 1995 British twin study.

The concordance rate for narrowly defined (genotype concordance and phenotype concordance)in identical twins is about 60% in all three studies. About 1/3rd of identical twins demonstrate clinical heterogeneity (genotype concordance and phenotype discordance). That 1/3 of identical twins demonstrated clinical heterogeneity is a huge problem for the genetic determinists and may be related to the fact that about 2/3rds of identical twins share the same prenatal environment (single placenta) while 1/3 of identical twins do not share exactly the same prenatal environmnet (seperate placenta).

This new twin study supports Rutter’s hypothesis of a ‘two-hit’ mechanism operating in autism etiology.

The hypothesis states that the genetic influences underlying the broad autism phenotype (autistic-like traits) are not the same as the genetic and environmental factors involved in the disruption of early brain development.

In my view, The two hit mechanism also implies that the seperate genetic influences underlying the broad autism phenotype is a background genetic effect on the neuroanatomical alterations involved in the transition to the handicapping disorder.

The CATS study group is the first who has promised to record chorion data (placentation status) and it will be interesting in their final report if they have been successful in recruiting a large enough enough sample of identical twins with unambigous chorion data and whether dichorion type (seperate prenatal environment) is associated with clinical heterogeneity.

The most compelling argument for Rutter’s two hit hypothesis comes not from environmental research but rather amazingly from genetic research.

Years ago Ghaziuddin (1997, 2000) compared a group of Downs Syndrome children and their first degree relatives (parents and siblings) with or without co-occurring autism. In Downs Syndrome with co-occurring autism there was an excess of first degree relatives who met the description of BAP type features compared to first degree relatives in Downs Syndrome without co-occurin autism who did not. The Downs Syndrome mutation was not present in first degree relatives, parents and siblings, and the genetic influences underlying the BAP component has to be a familial separate component consistent with the two-hit hypothesis. Downs Syndrome may not be at all inherited but Downs Syndrome with co-occurring autism paradoxically does strongly suggest the likelihood of a Gene X Gene synergistic etiology further obfuscating the entire concepts of ‘genetics’ and ‘heritability’ that are all too frequently used by the genetic determinists as if they were interchangeable concepts.

Classical twin studies are rather simplistic and compare concordance rates in identical twins to concordance rates in fraternal then calculate a ‘heritability estimate’.

In 1992 Torre reviewed the literatue and identified all twins with Downs Syndrome and found that concordance for Down’s Syndrome in identical twins is 98% (18 of 19 cases). Concordance rates for Down’s Syndrome in fraternal twins were 2% (2 out of 127 cases).
Using classical twin study calculations Down’s Syndrome would appear to be the most ‘heritable’ of all the developmental disorders with a calculated heritabily estimate substantially higher the the ‘heritability estimates’ for either autism or schizophrenia.

The only problem is that Down’s Syndrome isn’t heritable at all and is almost always the consequence of a germline reproductive error (egg or sperm) and the Down’s Syndrome mutation is not present in either parent. Risk for Downs Syndrome re-occurance in families with a Down’s Syndrome child is no higher than the risk for Down’s Syndrome in the gneral population about or less than 1%.

So naturally there is rarely a difference between ASD and non ASD kids!
The ability to comprehensively measure Hg blood levels is so primitive. Let’s work on that before telling families there is nothing to worry about.

Taking a onetime blood sample is rarely helpful!!!

I take monthly random urine tests and have them tested for porphryins. I use myself and my NT child as controls. My regressive ASD son’s urine used to show heavy metals, literally, off the charts.

I have worked hard detoxing Christian and have seen a great improvement, especially in his health. As the Hg and AL burden in his body lessened he became much healthier and more cognitively aware.

I read with interest the following, “On the other hand, a previously identified factor, maternal infection, was not associated (4). Why not? The researchers suggested that fever, not infection per se, may be a factor. Using self-report and medical records obtained prior to study entry may not accurately capture all relevant information, and an infection or fever may be missed in some reports.”

My son, now age 9, was diagnosed with ASD prior to age 3. During his childbirth, I “spiked” a very high fever. There were a few other complications as well. I have never seen his/our childbirth records. After I order these records, is there some place I can submit them to add to the data collected (I did not give birth to twins).

You state: “Using this approach, the researchers found that the concordance of severe autism between identical twins and fraternal twins was about the same, indicating a strong environmental component to ASD severity”. Where does this assertion come from? The published paper describing this study (Hallmayer et al, Arch Gen Psych, published online July 4th 2011) gives concordance rates in identical twins as consistently about TWICE those in fraternal twins (regardless of sex and whether the diagnosis used was strict autism or autistic spectrum disorder). These data are completely consistent with those from many other studies (including a number of other recent ones) and give strong evidence for high heritability and very little evidence for major environmental effects.